Empagliflozin Increases Cardiac Energy Production in Diabetes

Verma, Subodh; Rawat, Sawan Kumar; Ho, Kim L.; Wagg, Cory S.; Zhang, Liyan; Teoh, Hwee; Dyck, John E.; Uddin, Golam Mezbah; Oudit, Gavin Y.; Mayoux, Eric; Lehrke, Michael; Marx, Nikolaus; Lopaschuk, Gary D.

doi:10.1016/j.jacbts.2018.07.006

Cited by 282 publications

(174 citation statements)

References 37 publications

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“…Various hypotheses have been advanced to explain these effects, for example, the increased ketone concentrations found with SGLT2 inhibitor use. Since ketones are optimal substrates for all tissues, including the heart, as they require less oxygen (than FFAs) for oxidation, Ferrannini et al 46 49 Other hypothesized mechanisms include decreased blood pressure, 50 plasma volume, 51 a re-arrangement of myocardial electrolyte handling 52 and many others. None of these, however, has been completely convincing, and the main mechanism(s) promoting the beneficial cardiovascular effects remains unclear.…”

Section: Sglt2 Inhibitorsmentioning

confidence: 99%

Sodium‐glucose co‐transporter inhibitors: Medications that mimic fasting for cardiovascular prevention

Giaccari

2019

Diabetes Obesity Metabolism

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Recent evidence that some diabetes drugs can prevent cardiovascular disease (CVD) has profoundly modified the treatment approach to type 2 diabetes mellitus. Sodium‐glucose co‐transporter‐2 (SGLT2) inhibitors and almost all glucagon‐like peptide‐1 receptor agonists (GLP‐1RAs) have been shown, beyond their effect on glucose control, to lead to a significant decrease in the cardiovascular burden of diabetes. Although these results are well known, the mechanisms of action by which they prevent cardiovascular events are still poorly understood. Both GLP‐1RAs and SGLT2 inhibitors promote weight loss, although through different mechanisms. SGLT2 inhibitors promote glycosuria, leading to significant caloric deficit and weight loss. Similarly, GLP‐1RAs, probably through an anorexic effect on certain brain areas, inhibit calorie intake, with ensuing weight loss. Although it features less prominently in current treatment pathways, pioglitazone has also demonstrated cardiovascular benefits. Pioglitazone profoundly modifies several mechanisms and risk factors responsible for CVD; however, these mechanisms certainly do not include weight loss. Obesity, and consequent insulin resistance, are well known risk factors for CVD, and it would appear logical to attribute the positive cardiovascular effects of these two classes of drugs to weight loss. The direct metabolic effects of these two classes, however, are profoundly different. The present review proposes a unifying hypothesis to explain the reduction in CVD through three different mechanisms of curbing free fatty acid excess, all leading to the common mechanism of cellular caloric restriction. If this hypothesis is correct, the excellent results obtained with SGLT2 inhibitors could be attributed to their close simulation of fasting.

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Section: Sglt2 Inhibitorsmentioning

confidence: 99%

Sodium‐glucose co‐transporter inhibitors: Medications that mimic fasting for cardiovascular prevention

Giaccari

2019

Diabetes Obesity Metabolism

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“…In a recent clinical trial, the beneficial effect of sodium glucose co‐transporter‐2 (SGLT2) inhibitor empagliflozin on cardiovascular outcome in patients with diabetes was also thought to be associated with hyperketonemia . However, recent studies showed that despite hyperketonemia, empagliflozin either lowered or did not alter myocardial ketone body utilization in rodent models of diabetes.…”

Section: Introductionmentioning

confidence: 99%

“…Hyperpolarized 13 C magnetic resonance spectroscopy ( 13 C-MRS) is a powerful technique to study metabolism non-invasively in vivo.…”

mentioning

confidence: 99%

“…We used hyperpolarized [3][4][5][6][7][8][9][10][11][12][13] C]acetoacetate as a novel probe for ketone body metabolism, 12 hyperpolarized [1-13 C]butyrate as a probe for short chain fatty acid metabolism, 25 and [1-13 C] pyruvate as a probe for glucose metabolism, 26 to comprehensively study the effects of cardiac metabolic modulations upon KD feeding (see pathways in Figure 1). Upon administration of the hyperpolarized probes, the production of downstream metabolites as a result of the metabolism of the 13 C substrate can be observed in real time using 13 C-MRS within 1 minute of substrate administration. 27 As an in vivo method, hyperpolarized 13 C-MRS allows investigation of cardiac metabolism in a more physiological condition compared with, for example, ex vivo perfused heart experiments.…”

mentioning

confidence: 99%

“…Upon administration of the hyperpolarized probes, the production of downstream metabolites as a result of the metabolism of the 13 C substrate can be observed in real time using 13 C-MRS within 1 minute of substrate administration. 27 As an in vivo method, hyperpolarized 13 C-MRS allows investigation of cardiac metabolism in a more physiological condition compared with, for example, ex vivo perfused heart experiments. The in vivo and non-invasive nature of the technique also allows the measurements of the same animals under different conditions, for example, at rest or under stress conditions.…”

mentioning

confidence: 99%

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Cardiac metabolic modulation upon low‐carbohydrate low‐protein ketogenic diet in diabetic rats studied in vivo using hyperpolarized ¹³C pyruvate, butyrate and acetoacetate probes

Abdurrachim

Teo

Woo

et al. 2019

Diabetes Obesity Metabolism

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Aim: To investigate the effects of long-term low-carbohydrate low-protein ketogenic diet (KD) on cardiac metabolism and diabetic cardiomyopathy status in lean diabetic Goto-Kakizaki (GK) rats.Materials and Methods: Diabetic GK rats were fed with KD for 62 weeks. Cardiac function and metabolism were assessed using magnetic resonance imaging and 13 C magnetic resonance spectroscopy ( 13 C-MRS), at rest and under dobutamine stress. 13 C-MRS was performed following injection of hyperpolarized [3-13 C]acetoacetate, [1-13 C]butyrate or [1-13 C]pyruvate to assess ketone body, short-chain fatty acid or glucose utilization, respectively. Protein expression and cardiomyocyte structure were determined via Western blotting and histology, respectively.Results: KD lowered blood glucose, triglyceride and insulin levels while increasing blood ketone body levels. In KD-fed diabetic rats, myocardial ketone body and glucose oxidation were lower than in chow-fed diabetic rats, while myocardial glycolysis and short-chain fatty acid oxidation were unaltered. Dobutamine stress revealed an increased cardiac preload and reduced cardiac compliance in KD-fed diabetic rats. Dobutamine-induced stimulation of myocardial glycolysis was more enhanced in KD-fed diabetic rats than in chow-fed diabetic rats, which was potentially facilitated via an upregulation in basal expression of proteins involved in glucose transport and glycolysis in the hearts of KDfed rats. The metabolic profile induced by KD was accompanied by cardiac hypertrophy, a trend for increased myocardial lipid and collagen content, and an increased marker of oxidative stress.Conclusion: KD seems to exacerbate diabetic cardiomyopathy in GK rats, which may be associated with maladaptive cardiac metabolic modulation and lipotoxicity. K E Y W O R D S13 C magnetic resonance spectroscopy, diabetes, hyperpolarized 13 C substrates, ketogenic diet, myocardial substrate metabolism

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Renal Tubular Handling of Glucose and Fructose in Health and Disease

Vallon

Nakagawa

2021

Comprehensive Physiology

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Empagliflozin Increases Cardiac Energy Production in Diabetes

Abstract: Visual Abstract

Cited by 282 publications

References 37 publications

Sodium‐glucose co‐transporter inhibitors: Medications that mimic fasting for cardiovascular prevention

Sodium‐glucose co‐transporter inhibitors: Medications that mimic fasting for cardiovascular prevention

Cardiac metabolic modulation upon low‐carbohydrate low‐protein ketogenic diet in diabetic rats studied in vivo using hyperpolarized ¹³C pyruvate, butyrate and acetoacetate probes

Renal Tubular Handling of Glucose and Fructose in Health and Disease

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Empagliflozin Increases Cardiac Energy Production in Diabetes

Abstract: Visual Abstract

Cited by 282 publications

References 37 publications

Sodium‐glucose co‐transporter inhibitors: Medications that mimic fasting for cardiovascular prevention

Sodium‐glucose co‐transporter inhibitors: Medications that mimic fasting for cardiovascular prevention

Cardiac metabolic modulation upon low‐carbohydrate low‐protein ketogenic diet in diabetic rats studied in vivo using hyperpolarized 13C pyruvate, butyrate and acetoacetate probes

Renal Tubular Handling of Glucose and Fructose in Health and Disease

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Product

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About

Cardiac metabolic modulation upon low‐carbohydrate low‐protein ketogenic diet in diabetic rats studied in vivo using hyperpolarized ¹³C pyruvate, butyrate and acetoacetate probes